INITIAL EXPERIENCE OF THE ENZALUTAMIDE TREATMENT FOR CASTRATION-RESISTANT PROSTATE CANCER.

(Objective) Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with castration-resistant prostate cancer (CRPC). We retrospectively evaluated clinical efficacy and safety of enzalutamide in CRPC. (Patients and methods) We reviewed clinical records of 73 patients who had received enzalutamide for the CRPC at Showa University and affiliated 7 hospitals. Enzalutamide was given at a dose of 160 mg/day, but some patients were treated at lower dose because of there age or poor performance status. Prostrate-specific antigen (PSA) response, prior docetaxel use and the previously administered agents were evaluated retrospectively. (Results) The median patients age was 77 years, the median Gleason score was 9 and the median PSA level at baseline was 26.9 ng/ml. The patients who had prior docetaxel use were 29 (39.7%) and the median of total docetaxel dose was 460 mg/body. The median number of total prior treatments (anti-androgens, Estramustine and steroid) was 3. Twenty seven (61.4%) patients with docetaxel-naïve achieved over 50% reduction of PSA level from baseline, but only 7 (24.1%) in patients previously treated with docetaxel. The most common adverse events included fatigue (24.7%), anorexia (24.7%) and the nausea (16.4%). We found a small proportion of responders to enzalutamide experienced a PSA flare. (Conclusion) Our results of the use of Enzaltamide for CRPC were similar with previous reports. PSA flare was found in some patients with CRPC who responded to enzaltamide. It should be noted that this possible PSA flare phenomenon.

[A CASE OF PROSTATE CANCER WITH UNUSUAL PATTERN OF RECURRENCE AFTER RADIOTHERAPY].

An 82-year-old man underwent radiotherapy (brachytherapy, external beam radiotherapy) for prostate cancer, followed approximately five years later by endocrine therapy for biochemical recurrence, which controlled the prostate-specific antigen (PSA) level. His later admission due to severe gross hematuria and dysuria is described. Computed tomography and magnetic resonance imaging findings revealed a cystic tumor continuous with the prostate between the prostate and rectum, and this tumor was thought to be the cause of the hematuria and dysuria. Transrectal biopsy and transurethral resection of the prostate were performed for pathological diagnosis and improvement of dysuria. The pathological diagnosis was remnant prostate cancer, and the cystic tumor was thought to have developed as a result of prostate cancer recurrence. Although chemotherapy using docetaxel was considered postoperatively, the patient refused this treatment. Even though the PSA level was under control, the patient's condition progressed rapidly, with onset of pulmonary and cervical lymph node metastases within a short period of time, and the patient subsequently died.

Enhancement of IL-2-induced cytotoxicity by interferon-alpha in renal cell carcinoma.

Metastatic renal cell carcinoma (mRCC) treatment consists of molecular targeted agents and cytokines that have fundamentally different mechanisms of action. Clinical responses also differ; complete response is rare with molecular targeted agents but is sometimes achieved with cytokine therapies. Because of the relatively high efficacy of combination therapy with low-dose interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) against mRCC, it is important to reevaluate cytokine therapies in vitro. Here, we show that when IL-2 is administered in combination with IFN-alpha, a stronger cytotoxic effect of PBMCs on RCC cell lines is observed than when IL-2 is administered alone. The upregulation of TNF-related apoptosis-inducing ligand on NK cell by IL-2 and suppression of regulatory T cells (Tregs) by IFN-alpha were recognized at the same time when cytotoxicity of peripheral blood mononuclear cells (PBMCs) was enhanced. IL-2 is known to activate natural killer cell cytotoxicity; however, IL-2 also stimulates Treg expansion, which enhances immunosuppression. On the other hand, IFN-alpha negatively regulates Treg cells, thereby increasing the function of immune effector cells. Our in vitro results may explain, at least in part, the clinical efficacy of combination low-dose IL-2 and IFN-alpha therapy against mRCC.

Surgical challenges of Castleman's disease of the pelvis.

Castleman's disease (CD) is a unique lymphoproliferative disorder. It commonly occurs in the mediastinum, neck, axilla, and abdomen, and retroperitoneal involvement is rare. Here we report a unique case of CD in the pelvis. Laparotomy was performed and surgery was complicated by adhesions and vascularity. Total surgical duration was Five hours and 45 min with 4.5 L of blood loss. Ten pints of blood was transfused. The mass was histopathologically diagnosed as hyaline-vascular CD. The patient was free of recurrence after 10 years of follow-up.

Zoledronate stimulates gamma delta T cells in prostate cancer patients.

Androgen deprivation therapy is the mainstay of treatment for prostate cancer. Given its frequent failure, new therapy that reduces prostate cancer progression would be a breakthrough in treating this disease. Bisphosphonates are well-established agents for treating skeletal-related events (SREs) in prostate cancer patients with bone metastases. Exposure to bisphosphonates may not only reduce the incidence of SREs, but also have anticancer effects by modulating a patient's immunity. The purpose of this study was to examine the effect of zoledronate (ZOL) on gamma delta T cells, serum prostate-specific antigen (PSA) levels, and velocities. The effect of ZOL, with and without IL-2, on gamma delta T cell activation was examined in vitro. Furthermore, the activated state and the number of gamma delta T cells and changes in serum PSA levels were examined for patients who received ZOL infusion for the prevention of SREs. We found that ZOL activated gamma delta T cells, and the number of gamma delta T cell was increased when IL-2 was administered with ZOL in vitro. Comparisons before and after the first ZOL infusion revealed that gamma delta T cells in peripheral blood were activated by ZOL. Moreover, after the first ZOL treatment, reduction in serum PSA was observed in 3 of 11 patients, and reduction in PSA velocity was observed in 5 of 10 patients. Our findings indicate that ZOL stimulates gamma delta T cells in vivo and in vitro. This study provides further insight into the ability of gamma delta T cells to induce an antitumor immune response.

Prostate cancer detection rate and Gleason score in relation to prostate volume as assessed by magnetic resonance imaging cognitive biopsy and standard biopsy.

OBJECTIVE: This study aimed to assess the relationship of the prostate cancer and Gleason scores (GSs) or ISUP Grade system with prostate volume (PV) as assessed by magnetic resonance imaging (MRI) cognitive biopsy and standard biopsy. MATERIAL AND METHODS: Data were collected from 659 patients who underwent MRI cognitive biopsy and standard biopsy from January 2014 to January 2018. The biopsies were performed because of increased prostate-specific antigen (PSA) levels (>4 ng/mL) and/or abnormal digital rectal examination findings. Transrectal ultrasound was used to measure PV. RESULTS: Prostate cancer detection rates in patients with increased PVs of ≤40 cc and >40 cc were 68.8% and 51.6% (p<0.001), respectively. ISUP Grade group ≥2 (Gleason score ≥3+4) detection rates for increased PVs of ≤40 cc and >40 cc were 68% and 73%, and 22.3% and 37.8%, respectively, for those with ISUP Grade group ≥4 (Gleason score ≥8) (p=0.003). Among the patients with PV>40 cc, univariate logistic regression showed a significant relationship between ISUP Grade group ≥2 and PSA, free/total PSA, PSA density, and MRI (p<0.05). On multivariable logistic regression, MRI (p=0.014) and PSA (p=0.039) predicted ISUP Grade group ≥2 in patients with PV>40 cc. CONCLUSION: Although the detection rates of prostate cancer decreased as PV increased, the detection of prostate cancer aggressiveness increased as PV increased. This increase in high ISUP Grade lesions with the rise in PV is due to the use of MRI during prostate biopsy with standard biopsy.

A Novel, Circulating Tumor Cell Enrichment Method Reduces ARv7 False Positivity in Patients with Castration-Resistant Prostate Cancer.

BACKGROUND: The AR-V7 splice variant is a cause of castration-resistant prostate cancer (CRPC). However, testing for the presence of AR-V7 by real-time polymerase chain reaction (RT-PCR) shows AR-V7 positivity in healthy individuals. We hypothesized that the positivity reflects contamination by hematopoietic cells. We tried a novel circulating tumor cell (CTC) enrichment instrument, using Celsee, to clear hematopoietic cells. METHODS: We tested whole blood or Celsee-enriched samples for AR-V7 by RT-PCR, and included samples from 41 CRPC patients undergoing sequential therapy. We evaluated the associations between AR-V7 status and clinical factors. We evaluated factors affecting AR-V7 positivity. RESULTS: AR-V7 positivity was lower in Celsee-enriched than in whole blood specimens. AR-V7 and clinical factors did not predict the therapy effectiveness. We found no significant differences in the effectiveness of enzalutamide/abiraterone (Enz/Abi) upon AR-V7 evaluation. All AR-V7 positive patients had resistance to Enz/Abi. Docetaxel (DTX), cabazitaxel (CBZ), and Radium223 treatment showed no significant difference in the treatment effectiveness, regardless of AR-V7 presence. AR-V7 was more frequently positive than Extent of disease (EOD) 2 in cases with bone metastases. CONCLUSION: Celsee CTC enrichment suppresses AR-V7 false positivity. All AR-V7 positive patients presented resistance to Enz/Abi. DTX, CBZ, and Radium223 were effective and remain treatment options. AR-V7 positivity should progressively appear in patients with advanced bone metastases.

Expression of the fluoropyrimidine-metabolizing enzymes in bladder cancers as measured by the Danenberg tumor profile.

5-Fluorouracil (5-FU) and its prodrugs are used to treat various cancers. Response to 5-FU-based chemotherapy and expression of 5-FU-related enzymes differ among cancers. The objective of the present study was to investigate the relationship between the expression of 5-FU-related enzymes and clinicopathologic factors in bladder cancer. Formalin-fixed, paraffin-embedded sections of 44 bladder cancers and 27 normal bladders were included in this study. After laser capture microdissection, "Danenberg tumor profile," was performed for the measurement of 5-FU-related enzymes. There was no significant difference between dihydropyrimidine hydrogenase (DPD) mRNA expression in bladder cancer and in normal bladder. On the contrary, mRNA expressions of orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), and thymidine phosphorylase (TP) in bladder cancer were higher than those in normal bladder. Compared with previously reported DPD mRNA expressions in other types of cancer, DPD mRNA expression in bladder cancer was relatively low. The 5-FU-related enzymatic condition of bladder cancer is favorable for 5-FU.

A pilot study of quality of life of patients with hormone-refractory prostate cancer after gene therapy.

BACKGROUND: The effects on quality of life (QOL) after a Phase I/II clinical trial of a combination of osteocalcin promoter-driven herpes simplex virus thymidine kinase (Ad-OC-TK) gene therapy and valacyclovir (VAL) were investigated for patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: The QOL of six patients was prospectively assessed after gene therapy on days 0, 14, and 28. A modified questionnaire was created based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire's prostate cancer-specific module (EORTC QLQ-PR25). RESULTS: The scores of all items significantly improved along with the total score. Further, bodily pain was significantly reduced on day 28. Moreover, the rate of change in the serum prostate-specific antigen levels from day 0 to day 28 was significantly correlated with the rate of change in bodily pain. CONCLUSION: In this clinical trial, Ad-OC-TK plus VAL treatment significantly improved the short-term QOL and bodily pain of patients with localized recurrence or bone metastases of HRPC.

Development of a Highly Sensitive Technique for Capturing Renal Cell Cancer Circulating Tumor Cells.

PURPOSE: Liquid biopsy is becoming increasingly important as a guide for selecting new drugs and determining their efficacy. In urological cancer, serum markers for renal cell and urothelial cancers has made the development of liquid biopsy for these cancers strongly desirable. Liquid biopsy is less invasive than conventional tissue biopsy is, enabling frequent biopsies and, therefore, is considered effective for monitoring the treatment course. Circulating tumor cells (CTCs) are a representative liquid biopsy specimen. In the present study, we focused on developing our novel technology for capturing renal cell cancer (RCC)-CTCs using an anti-G250 antibody combined with new devices. Basic experiments of our technology showed that it was possible to detect RCC-CTC with a fairly high accuracy of about 95%. Also, RCC-CTC was identified in the peripheral blood of actual RCC patients. Additionally, during the treatment course of the RCC patient, change in the number of RCC-CTC was confirmed in one case. We believe that the technology we developed will be useful for determining the treatment efficacy and drug selection for the treatment of renal cell cancer (RCC). In order to solve issues such as thresholds setting of this technology, large-scale clinical trials are expected.

Use of the CellSearch Circulating Tumor Cell Test for monitoring urothelial cancer: two case reports of metastatic urothelial cancer.

Until now, there have been no reliable serum markers for monitoring urothelial cancers. However, it has been reported that it is possible to detect circulating urothelial cancer cells using the CellSearch Circulating Tumor Cell (CCTC) Test (Immunicon, Huntingdon Valley, PA). This case report is a representative example of the good correlation between the change of the number of circulating tumor cells in the blood and the state of an urothelial cancer after therapies. Detection of circulating tumor cells might be a valuable serum marker for urothelial cancer patients with distant metastasis.

Systematic review and two new cases of primary upper urinary tract neuroendocrine carcinomas.

BACKGROUND: Upper urinary tract neuroendocrine carcinoma (UUT-NEC) is extremely rare and has a poor prognosis. Although a few cases of successful treatment have been reported, no treatment has shown established efficacy. PATIENTS AND METHODS: We analyzed 70 UUT-NEC patients, including 68 with small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) reported between 1985 and 2017 and 2 treated at our hospital. RESULTS: Median patient age was 66 years, 58.6% were men, and 60% were of Asian descent. Most UUT-NECs were SCNEC (68; 95.7%), whereas LCNEC was very rare (2; 2.9%). More than half of the patients had accompanying other histological components, the most common being urothelial carcinoma (51.5%), whereas 41.4% had NEC alone. Of the 70 patients, 27 underwent additional therapy (e.g., chemotherapy and radiotherapy) along with surgery. Median survival was 15 months. In univariate analysis, stages T1-2 disease showed better prognosis than stages T3-4 (P < 0.001). Additional treatment (e.g., chemotherapy and radiotherapy) significantly improved prognosis (P = 0.014). Moreover, platinum-based chemotherapy also was associated with improved prognosis (P = 0.017). For platinum-based chemotherapy, multicollinearity with additional treatments was strong, and, thus, these data were not included in the analysis. Multivariate analysis revealed pathological stage (T1-2 vs. T3-4; P = 0.003) and additional treatment (P = 0.028) to be independent predictors of improved prognosis. CONCLUSION: Although UUT-NEC has a poor prognosis, additional treatment along with surgery and therapeutic intervention and stage T1-2 disease are independent factors to improve prognosis.

[Immunohistochemical analysis of CD83, CD8 and CD4 positive cells in renal cell carcinoma].

OBJECTIVES: In order to evaluate the immunological milieu in renal cell carcinoma (RCC), we investigated infiltration by mature dendritic cells (CD83 positive cells), cytotoxic-T cells (CD8 positive cells) and helper-T cells (CD4 positive cells) in RCCs, as well as in surrounding normal tissues and correlations between the cell types. MATERIALS AND METHODS: Specimens from 33 surgically resected RCCs were embedded in paraffin and then stained for CD4, CD8, CD83. Each section contained three areas, tumor tissue, tumor margin and normal renal parenchyma. Cells positive for CD4, CD8 and CD83 were counted each area. RESULT: Cells positive for CD4, CD8 and CD83 were observed predominantly in the tumor margins, rather than tumor tissue and normal renal parenchyma. The differences were significant in the number of immune positive cells between tumor margin and tumor tissue, and between tumor margin and normal renal parenchyma. A significant correlations was found between CD4 and CD83 positive cells (r = 0.805, p < 0.0001), and also between CD8 and CD83 positive cells (r = 0.505, p < 0.0001). CONCLUSION: It has been reported that mature dendritic cells induces cytotoxic-T cell and helper-T cell responses. Infiltrating mature dendritic cells, cytotoxic-T cells and helper-T cells were present only in the tumor margin. This may reflect significant immune reaction around the tumor margin.

[MHC-class I expression on prostate carcinoma and modulation by IFN-gamma].

OBJECTIVES: In this study, we investigated MHC-class I expression on both prostate cancer and normal prostate and compared those data with the number of CD8+ lymphocyte. Secondary, we investigated effect of IFN-gamma to the MHC-class I expression on prostate carcinoma. MATERIALS AND METHODS: Twenty cryo-preserved benign prostate samples (Seven normal prostates and five benign prostatic hypertrophy samples.) and fifteen prostate carcinoma samples were used for immunohistochemistry of CD8 and MHC-class I. Eleven fresh single cell suspensions of prostate carcinoma were used for IFN-gamma study. After 24 hours IFN-gamma stimulation, MHC-I expression was measured by FACs analysis. RESULTS: Interestingly, significant correlation was observed between MHC-class I expression and the CD8+ lymphocyte infiltrate (r = 0.705, P < 0.0001). After 24 hrs IFN-gamma stimulation, MHC-class I expression was up-regulated in all samples (p < 0.05). CONCLUSION: Reduced expression of MHC-class I was thought as one of the factor which is related to the reduced degree of TILs (tumor infiltratig lymphocytes) in prostate cancer. IFN-gamma which is secreted mainly from CTL (cytotoxic T lymphocyte) might increase the degree of TIL through up-regulated MHC-class I.

Complete response to low-dose sorafenib in a patient with metastatic renal cell carcinoma: A case report.

We present a case of a patient with metastatic renal cell carcinoma (mRCC) who was treated solely with low-dose sorafenib and achieved a complete response (CR). A 79-year-old man with cytokine-refractory mRCC involving the lung, abdominal wall and lymph nodes was treated with low-dose sorafenib (400 mg/day) as a second-line therapy. Five months into treatment, CR was confirmed by follow-up computed tomography. No severe adverse events were observed and sorafenib treatment was continued without appearance of new lesions. Although sorafenib has been approved for mRCC treatment, complete clinical recovery is uncommon and has rarely been described. In this case, low-dose sorafenib appears to be sufficient for achieving CR while suppressing toxicity. Furthermore, long-term continuous administration induces the patient to obtain disease stabilization. However, considering toxicity and treatment costs, it is debatable whether treatment should be discontinued or sustained after CR.

Impalement injury of the urinary bladder: a case report.

Impalement injury of the urinary bladder, especially secondary to rectal impalement, is extremely rare. In this case, a 31-year-old man sustained a steel pipe impalement injury through his perirectal region. He presented with gross hematuria, abdominal defense, and a penetrating wound. On the basis of the computed tomography findings and abdominal defense, we suspected a through-and-through bladder perforation from the rectal space to the intraperitoneum. Laparotomy revealed a through-and-through bladder perforation as well as damage to the right ureter, 3 distinct ileal injuries, and rectal anterior, anal, and right seminal vesicle injuries. Surgical repair of each damaged site was undertaken. The prompt diagnosis and surgical repair ensured good postoperative recovery.

The antitumour effect of {gamma}{delta} T-cells is enhanced by valproic acid-induced up-regulation of NKG2D ligands.

UNLABELLED: The aim of this study wsa to evaluate the additive effect of valproic acid (VPA) to γδ T-cell cytotoxicity against bladder cancer cells. MATERIALS AND METHODS: Human bladder cancer cell lines TCCSUP and 253J were treated with VPA and mRNA expression of natural killer group 2D (NKG2D) ligands was determined. The antitumour effect of expanded γδ T-cells against zoledronic acid (ZOL) and VPA pre-treated cancer cells was subsequently determined. RESULTS: VPA increased mRNA expression of NKG2D ligands on both cancer cell types. A blocking study revealed that 253J cells were recognised through NKG2D, while TCCSUP cells were mainly recognised through γδ T-cell receptor. VPA pre-treatment increased sensitivity to cytolysis by γδ T-cells for both cancer cell types, whereas ZOL pre-treatment was only effective against TCCSUP. CONCLUSION: Induction of NKG2D ligands by VPA increased the susceptibility of cancer cells that are recognised by NKG2D to cytolysis by γδ T-cells.

Improving gene transfer in human renal carcinoma cells: Utilization of adenovirus vectors containing chimeric type 5 and type 35 fiber proteins.

The transduction efficacy of adenovirus serotype 5 (Ad5) vector in human renal carcinoma cells is generally low due to the down-regulated expression of Coxsackie and adenovirus receptor (CAR) in target cells. By contrast, the infectivity of adenovirus serotype 35 vectors depends on the binding rate to CD46 receptor, independent of CAR. In this study, we examined whether an adenovirus vector containing chimeric type 5 and type 35 fiber proteins (Ad5/F35) increases transduction efficiency compared to Ad5 vector in human renal carcinoma cells in vitro. The expression of CAR was much lower in the human renal carcinoma cells than in control HEK293 cells. By contrast, the expression of CD46 was similar and perhaps at a higher level in the human renal carcinoma cells than in the HEK293 cells. The transduction efficacy of Ad5/F35 vector was dramatically higher compared to that of Ad5 in human renal carcinoma cells, and was correlated to the expression of CD46. Thus, Ad5/35 vector may be useful for the development of novel gene therapy approaches to renal cell carcinoma.

Improved gene transfer into renal carcinoma cells using adenovirus vector containing RGD motif.

UNLABELLED: The transduction efficacy of adenovirus serotype 5 (Ad5) vector in human renal carcinoma cells is generally extremely low due to the non-expression of Coxsackie and adenoviral receptor (CAR). We investigated whether fiber-modified Ad vector containing an RGD motif in the HI loop of the Ad fiber knob could increase the transduction efficiency of Ad5 in human renal carcinoma cells in vitro. MATERIALS AND METHODS: We examined both expressions of CAR, and alpha(v), beta(3) and beta(5) integrins, and the transduction efficacy of fiber-modified adenovirus vector in all cell lines. RESULTS: The expression of CAR was lower and those of alpha(v) and beta(3) integrins were higher in all cell lines compared with control cell line, KK47. The transduction efficacy of fiber-modified Ad vector increased by 125- to 1,800-fold compared with Ad5. CONCLUSION: The fiber-modified Ad vector may be useful to establish effective new gene therapy strategies for the treatment of renal cell carcinoma.